MATRIX-IPC 2022-029 A phase I/II study evaluating Tuvusertib (M1774), an ATR Inhibitor, in combination with fulvestrant in hormone receptors-positive and HER2-negative, advanced breast cancers, resistant to CDK4/6 inhibitor plus aromatase inhibitor-based endocrine treatment and with homologous recombination deficiency, oncogenic driver activation and/or other molecular alterations associated with replication stress (RS)

Prior treatment

• Has received previous fulvestrant
• Concomitant use of known strong or moderate CYP3A inducers
• Major surgery within 2 weeks of starting study treatment or an anticipated need for major surgery during the study...
• Any other clinical condition, uncontrolled concurrent illness, or other situations, which in the Investigator’s opinion would not make the patient a good candidate for the study or may potentially impact the absorption of M1774
• Live vaccines within 4 weeks of first dose of study intervention and while receiving study intervention.
• Patients unable to swallow orally administered medication
• Any investigational therapy within ≤ 21 days or 5 half-lives prior treatment, whichever is longer, prior treatment
• Any hormonal therapy within 7 days prior treatment (except ovarian function suppression)
• Any cytotoxic therapy within 21 days (3-weekly regimen), 14 days (weekly or oral regimen) prior treatment.
• Previous treatment with ATR or CHK1 inhibitors. Prior treatment with PARP inhibitor is allowed.
• Concomitant use of known strong cytochrome P (CYP) 3A inhibitors or moderate CYP3A inhibitors.

Other illness

• Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy
• HIV, HBV or HCV infection
• History or known hypersensitivity to the active substances or to any excipients of the study interventions.
• Patients with second primary cancer
• Cardiac or vascular diseases currently or within the last 6 months

Lab values

• Mean resting corrected QTc interval using the Fridericia formula

Other

• Visceral crisis or impending visceral crisis at time of screening.
• Pregnant or breast feeding women.
• Patient considered socially or psychologically unable to comply with the treatment and the required medical follow-up

• Age ≥ 18 years
  • Patient must have normal organ and marrow function
  • Adequate renal function
  • Female participant must have a negative serum pregnancy test.
  • Use of contraceptive if applicable
  • Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1.
  • . Patient affiliated to regimen of social security
  • Are capable of giving signed informed consent (or a trusted person).
  • Man or postmenopausal woman due to either surgical/natural menopause or chemical ovarian suppression.
  • Patient has advanced breast cancer
  • Patient has pathologically confirmed hormone receptors (HR)-positive and HER2-negative advanced BC. HER2- negative breast
  • Patient has disease progression while receiving aromatase inhibitor therapy in combination with CDK4/6 inhibitors
  • No more than one previous chemotherapy regimen for advanced disease.
  • No more than 1 previous endocrine therapy administered for metastatic disease.
  • Patient with gBRCA1/2 must have received PARP inhibitors and have experienced disease progression during or after treatment
  • ECOG Performance Status of 0 or 1.